OBJECTIVE: The purpose of this study was to assess whether a genetic variant associated with higher fibrinogen levels is associated with increased coronary heart disease (CHD) risk, as a test of the causal influence of fibrinogen on CHD. METHODS AND RESULTS: We performed a meta-analysis of case-control and prospective studies of the G-455-->A and C-148-->T beta-fibrinogen promoter region variants, in relation to CHD risk. The 19 studies found included 12,393 cases and 21,649 controls. Fibrinogen levels were robustly related to the genetic variants (mean increase per allele, 0.117 g/L; 95% CI, 0.091-0.142 g/L). However, the genetic variants were unrelated to CHD risk (odds ratio per allele, 0.976; 95% CI, 0.916-1.040). The predicted causal odds ratio for a 1 g/L higher plasma fibrinogen level, given the genetic variant-fibrinogen and genetic variant-CHD associations, was 0.81 (95% CI, 0.46-1.40). CONCLUSIONS: Although imprecise, the predicted causal effect of fibrinogen on CHD is clearly different from the odds ratio of 1.8 (95% CI, 1.6-2.0) for an increase of 1 g/L derived from a meta-analysis of observational studies. This evidence suggests that lowering the fibrinogen level may not, in itself, reduce CHD risk.